| 1. |
- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
- Jansen, I. E., et al.
(author)
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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 404-413
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
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| 3. |
- Hollnagel, Erik, et al.
(author)
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Modelling complex socio-technical systems : The Functional Resonance Analysis Method (FRAM)
- 2022
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In: Implementation Science. - London : Taylor & Francis. - 9780367626112 - 9780367626136 ; , s. 110-112
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Book chapter (other academic/artistic)abstract
- In a complex system, it is difficult to understand how the system works in order to analyse, manage, or improve it. A common solution to overcome this difficulty is to construct a model of the system. A model should be more than a diagram illustrating components of the system and how they are connected. The real purpose of a model is to represent the essential characteristics of something in a way that is amenable to analysis and manipulation. Currently, the leading method to develop a functional model is the Functional Resonance Analysis Method (FRAM). The FRAM provides a way to describe functions that can be used to develop a model of how a system performs. This method is based on four principles: 1) work that goes well and work that doesn’t happen in essentially the same way, 2) performance on all levels of an organization is variable because it must be adjusted to meet existing resources and demands, 3) acceptable and unacceptable outcomes both emerge from variability due to the everyday adjustments, which 4) can lead to functional resonance and non-linear consequences.
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| 4. |
- Hollnagel, Erik, et al.
(author)
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Work-as-Imagined and Work-as-Done
- 2022
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In: Implementation Science. - London : Taylor & Francis. - 9780367626112 - 9780367626136 ; , s. 175-177
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Book chapter (other academic/artistic)abstract
- Work-as-Imagined (WAI) and Work-as-Done (WAD) are two concepts borrowed from ergonomics. WAI represents how we think work should be done in order to achieve the intended outcomes. WAI covers our ideas about how others do, or should do, their work and also how we prepare our own work. In contrast, WAD represents the direct experience of those who actually do the work. Their understanding is detailed and precise, and their priorities are directly related to the work at hand, first and foremost to meet the goals of the activities for which they are responsible. The concepts of WAI and WAD make it possible to consider the difference between what people are expected to do and what they actually do without insisting that one is right and the other is wrong. The recognition of this difference is essential both for how work is managed and for how changes are planned and implemented. Managing work and changes to work must be grounded in a solid understanding of what actually goes on. When considering the gap between WAI and WAD, the solution should never be to make WAD comply with WAI. It is important, rather, to acknowledge the gap and to find ways to overcome it.
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